Solid dispersions of insoluble drug and preparation method thereof

ABSTRACT

The present invention relates to a solid dispersion characterized in that it comprises carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as an active ingredient and a water-soluble polymer having a glass transition temperature lower than the melting point of the active ingredient as a carrier, and it is prepared via melt extrusion. The solid dispersion of the present invention remarkably increases the solubility and dissolution rate of the active ingredient which is an insoluble drug to efficiently improve the bioavailability when it is orally administered.

TECHNICAL FIELD

The present invention relates to a solid dispersion that can be used forimproving bioavailability of an insoluble drug when it is orallyadministered, particularly a solid dispersion of the insoluble drug,carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, and apreparation method thereof.

BACKGROUND

Carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester is anazole derivative having the following formula:

It was filed as Korean Patent Application No. 2010-0016686. Thiscompound has a high protection efficacy for the nerve cell and thusshows a therapeutic effect to such diseases associated with the death ofnerve cells or neurodegeneration. However, since it has an extremely lowsolubility in water, it shows a very low bioavailability when orallyadministered.

Insoluble drugs show a low solubility and dissolution rate in thegastric juice, body fluids, etc. due to their low solubility in waterand thus their absorption through the gastrointestinal tract isinhibited to give a low bioavailability when they are orallyadministered. Thus, various approaches have been tried to improve thesolubility or absorptivity of the insoluble drugs. Examples thereofinclude converting the crystalline compound to its amorphous form,giving the physical change of increasing the surface area throughmicronization, or developing an emulsion or a microemulsion using asurfactant or a suitable solvent to increase the solubility andabsorptivity. Since the amorphous form has a higher water solubility—asmuch as 10-1600 times or more than the crystal form—if a compound isconverted to an amorphous form, its bioavailability may increaseremarkably. However, the amorphous form is highly apt to berecrystallized again to a crystal form having a low free energy with thepassage of time and thus has the disadvantage of low storage stability.The approach of increasing surface area through the micronization ofparticles may be effective in improving the solubility rate of suchcompounds having a low solubility rate. However, the intrinsicsolubility of a compound cannot be changed. Furthermore, themicronization using a mill such as a hammer mill or a jet mill can beapplied with some limitation depending on the energy reactivity of thecompound. Methods for improving solubility by preparing a microemulsionusing a solubilizer such as a surfactant are frequently applied, but theuse of a solubilizing agent, organic solvent or surfactant isconstrained due to their toxicity. As another method for improving thesolubility of insoluble drugs, researches using a solid dispersion havebeen tried. The solid dispersion is a system wherein the drug particlesare dispersed in the water-soluble polymer matrix in the solid phase. Itcan broaden the surface area of drug particles by reducing their size.Since the drug is converted to an amorphous form during the method ofpreparing the solid dispersion and thus exists partially or completelyin amorphous form, it is effective in terms of increasing the drugsolubility and its storage property. Spray-drying and melt-extrusionhave been known as methods for preparing the solid dispersion.Spray-drying is a method for preparing the solid dispersion by mixing adrug and a water-soluble polymer with a suitable solvent depending onthe characteristics of the drug and the water-soluble polymer, and thenspraying the mixture. The spray-drying method has the problem that it isdifficult to find a solvent that can dissolve the insoluble drug and thewater-soluble polymer together. Particularly, when the drug has a lowsolubility in the solvent selected, since a large amount of the organicsolvent should be used, the method can hardly be applied in commercialproduction and may cause the problems of solvent recovery andenvironmental pollution. The melt-extrusion is a method for formingsolid dispersion by melting a mixture of drug and water-soluble polymerat the temperature of the melting point of the drug and the glasstransition temperature of the polymer mixture or higher to convert thedrug into an amorphous form and by extruding it, endowing the polymerwith plasticity. The present inventors have found that a soliddispersion of an insoluble compound, whose solubility, bioavailabilityand physico-chemical stability are remarkably improved, can beeffectively prepared by using the melt-extrusion method under specificconditions. They then completed the present invention.

CITED PRIOR ART Patent Documents

Korean Patent Application No. 2010-0016686

Korean Patent Application No. 2010-0041436

DISCLOSURE OF INVENTION Technical Problem

The present invention provides a solid dispersion that can improve thesolubility and physico-chemical stability of the insoluble drug,carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester compound,and a preparation method thereof.

Solution to Problem

In order to solve the problem, the present invention provides a soliddispersion characterized in that it comprises carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as an active ingredientand a water-soluble polymer having the glass-transition temperaturelower than the melting point of carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a carrier, and it isprepared via melt extrusion. The solid dispersion of the presentinvention may further comprise a plasticizer.

The present invention also provides a method for preparing the soliddispersion by mixing the active ingredient carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester with the carrierwater-soluble polymer and by melt-extruding this mixture at atemperature lower than the melting point of the active ingredient. Inthe method according to the present invention, the mixture may furthercomprise a plasticizer.

Hereinafter, the present invention will be explained in greater detail.

The active ingredient carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (“CBI,” below) used inthe present invention is a substituted azole derivative having thefollowing formula. In the present invention, the term CBI is used ascomprising all the pharmaceutically acceptable salts, isomers, solvatesand combinations thereof.

CBI may be used for the purpose of prevention or treatment of diseasesselected from the group consisting of ictus, Alzheimer's disease,Huntington's disease, Parkinson's disease, Pick's disease,Creutzfeld-Jacob disease, Parkinson-ALS-dementia complex of Guam,Wilson's disease, multiple sclerosis, progressive supranuclear palsy,neuropathic pain and bipolar disorder, corticobasal degeneration,schizophrenia, attention deficit hyperactivity disorder, dementia,amyotrophic lateral sclerosis, retinal disease, epilepsy, stroke,transient ischemic attacks, myocardial ischemia, myoischemia, ischemiacaused by surgical technique associated with the extended stoppage ofcerebral blood flow, head trauma, spinal cord trauma, hypoxia anddepression.

The above active ingredient CBI is contained preferably in the amount of10 to 70 wt % based on the total weight of the composition. It is easyto secure the content homogeneity in the solid dispersion when theactive ingredient is contained in the amount of at least 10 wt %, andthe effect of improved bioavailability and the solubilization due to themixing with the polymer carrier can be achieved when the activeingredient is contained in the amount of 70 wt % or less.

In the solid dispersion of the present invention, the carrier mayinclude a water-soluble polymer having a glass transition temperaturelower than that of the active ingredient CBI, preferably polyvinylpyrrolidone and/or hypromellose acetate succinate, more preferablypolyvinyl pyrrolidone K30 as the polyvinyl pyrrolidone. Thewater-soluble polymer is contained preferably in the amount of 30 wt %or more, more preferably in the amount of 30 to 90 wt %, based on thetotal weight of the composition. Polyvinyl pyrrolidone having anymolecular weight can be used, but in particular those having themolecular weight of 30,000 to 60,000 are desired since they may buildthe viscosity which is easy for melt-extrusion.

The present invention may comprise a plasticizer. Any plasticizer thatcan facilitate the melt-molding can be used, but D-alpha-tocopherylpolyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 orboth of them can be preferably used. The plasticizer is used preferablyin the amount of 1 to 10 wt % based on the total weight of thecomposition.

As preferable embodiments of the present invention, there are providedsolid dispersions comprising the active ingredient CBI in 10 to 50 wt %and the water-soluble polymer polyvinyl pyrrolidone in 50 to 90 wt %, orcomprising the active ingredient CBI in 10 to 50 wt %, the water-solublepolymer polyvinyl pyrrolidone or hypromellose acetate succinate in 45 to85 wt % and the plasticizer D-alpha-tocopheryl polyethylene glycol 1000succinate (TPGS) or polyethylene glycol 400 in 1 to 5 wt %.

The present invention also provides a method for preparing theCBI-containing solid dispersion by mixing CBI, a water-soluble polymerand an optional plasticizer, and by melt-extruding this mixture at atemperature lower than the melting point of CBI. In particular, themethod of the present invention is characterized in that the soliddispersion is prepared by melt-extruding at a temperature lower than themelting point of the active ingredient CBI.

The above mixture is melted when it passes through four (4) or moreheating blocks whose temperature is sequentially lowered. Specifically,the mixture of drug and water-soluble polymer which have been mixed inadvance as a powder is introduced into an extruder and melt-extruded toprepare the solid dispersion of the present invention wherein theextruder is made of several heating blocks designed to be distinguishedfrom each other and which are connected in series. Here, thedistinguished heating blocks are controlled to have a temperature lowerthan the melting point of the melted drug—i.e., the active ingredientCBI. More preferably, the heating blocks consist of the first to fourthheating blocks wherein the melting temperature of the first heatingblock is controlled to 160 to 145° C., that of the second heating blockto 144 to 120° C., that of the third heating block to 119 to 80° C., andthat of the fourth heating block to 79 to 70° C.

From the earlier method of preparing a solid dispersion bymelt-extruding at a temperature which is conventionally higher—as muchas, for example, 15 to 30° C. or more—than the melting point of a drugfor the complete conversion of the drug to an amorphous form, thepreparation method of the present invention is different in that a soliddispersion is prepared by melt-extruding at a temperature lower than themelting point of the active ingredient CBI. Although the melting isperformed at a temperature lower than the melting point, the extrusionis performed through the specific sustained cooling and sequentialmelting by passing through the several heating blocks whose settingtemperatures are lowered sequentially. Thereby, the active ingredient issufficiently converted to an amorphous form even at a temperature lowerthan the melting point, and it is possible to prepare the soliddispersion showing an excellent dissolution pattern and bioavailabilityas illustrated in Table 13, and FIGS. 2 and 3. As explained above, sincethe solid dispersion is prepared by melt-extruding at a temperaturelower than the melting point of the active ingredient CBI in thepreparation method of the present invention, there is no possibility ofdecomposition or damage of the active ingredient CBI or the carrierpolymer used. Also, since the use of an organic solvent is not requiredfor preparing the dispersion, there is no concern about environmentalpollution or endangering the working environment. The solid dispersionprepared according to the present invention or the oral preparationcomprising the solid dispersion does not comprise any organic solvent,surfactant, etc. but comprises only the water-soluble polymer which isvery safe in the body, and thus it is very excellent in terms of safety.Furthermore, in comparison to the spray-drying method, the preparationmethod does not need the step of selecting an organic solvent and thusis simple.

The solid dispersion according to the present invention is extruded as asolid and may be solidified in the form of a long capillary. It ispulverized by using a suitable cutter or pulverizer so that it may beprepared in the form of a powder. This powder may be formulated in theform of a tablet capable of being administered into the human body orfilled into a gelatin capsule.

When the solid dispersion is formulated as an oral preparation for theconvenience of administration, it may comprise a pharmaceuticallyacceptable excipient. As the excipient, microcrystalline cellulose orlactose may be used as a diluent for achieving the desired volume, andmagnesium stearate, stearic acid or SiO₂ may be added as a lubricant forendowing the powder with fluidity and preventing mechanical adhesionduring filling of the capsule. Also, as a disintegrating agent forassisting the disintegration of a tablet, croscarmellose sodium, sodiumstarch glycolate and crospovidone may be used.

The solid dispersion according to the present invention conspicuouslyincreases solubility of the insoluble compound CBI in water. Thereby CBIshows a dissolution rate that satisfies the criteria of the DissolutionTest of Tablet (see Experiment 3). Also, as a result of apharmacokinetic test using Beagle dogs, the dispersion shows thesuperior bioavailability to CBI after its oral administration (seeExperiment 4).

Thus, the composition for oral administration and the pharmaceuticalcomposition, each of which comprises the solid dispersion of the presentinvention, can be effectively used for the treatment of the above-stateddiseases, against which CBI exhibits a therapeutic efficacy, inparticular the diseases of central nervous system including degenerativebrain disease.

Hereinafter, the present invention will be explained more in detail bythe Examples. However, the following Examples are only for theillustration of the present invention as specific types of techniques inthe practice thereof, and it is not intended that the scope of thepresent invention would be limited in any manner by them.

ADVANTAGEOUS EFFECTS

The solid dispersion of the present invention remarkably increases thesolubility and dissolution rate of the insoluble compound CBI toefficiently improve bioavailability when it is orally administered. Thepreparations containing the solid dispersion of the present inventionare physico-chemically very stable and have high storage stability.Furthermore, since the method for preparing the solid dispersionaccording to the present invention uses neither an organic solvent nor asurfactant, it is safe. The dispersion is melt-extruded at a temperaturelower than the melting point of the active ingredient, and thus there isno worry about decomposition or damage of the active drug or polymer,and the preparation method is simple.

DRAWINGS

FIG. 1 shows the results by Scanning Electron Microscopy for CBIobtained in Preparation 1 (left) and the CBI-containing solid dispersionof the present invention obtained in Example 1 (right).

FIG. 2 shows the results of the dissolution test of the soliddispersion-containing tablet obtained in Example 7.

FIG. 3 shows the pharmacokinetic profile observed after the soliddispersion of the present invention is orally administered to a Beagledog.

BEST MODE FOR CARRYING OUT THE INVENTION Preparation 1

Preparation of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethylester (CBI)

The preparation of carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (CBI) is described indetail in Korean Patent Application No. 2010-0041436. Specifically, itwas prepared as follows.

4-Benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved in a solventmixture of ethanol and water (3:1, 100 ml) in the concentration of 0.2 Mwhile stirring. NH₂OH—HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g,30 mmol) were added thereto, which was then stirred for about 30 min atroom temperature. The completion of reaction was confirmed by liquidchromatography, and water and ethanol were distilled off under reducedpressure to give a pale yellow solid compound. This solid compound wasextracted three times with water and ethyl acetate, and the organicsolvent layer was subjected to the condition of reduced pressure. Thecrude compound was recrystallized from hexane/ethyl acetate (10:1) togive a compound as a white solid. Thus obtained solid4-benzyloxy-benzaldehydeoxime (2.27 g, 10 mmol; a compound of 92%purity) was dissolved in methylene chloride (40 ml, 0.25 M), andpropargyl alcohol (1.77 ml, 30 mmol) was added thereto. To this solutionwas very slowly added in drops 10% NaOCl (13.7 ml, 20 mmol) at 0° C. byusing a dropping funnel. After all NOCl was added, the mixture wasstirred for about 5 h during which the temperature was slowly raised toroom temperature. After the completion of reaction was confirmed byliquid chromatography, the reaction mixture was distilled under reducedpressure to evaporate methylene chloride. Water (200 ml) was added tothe residue, and the resulting solid was filtered. The compound thusfiltered was washed with excess water and then finally washed withdiethyl ether. The solid compound thus obtained was recrystallized fromethyl acetate/hexane (1:2) to give[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white solid (Yield:2.5 g). Chlorosulfonyl isocyanate (1.04 ml, 12 mmol) was slowly added tothe THF solution (50 ml, 0.2 M) containing[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in a250 ml flask at −78° C. After disappearance of all the startingmaterials was confirmed by liquid chromatography, water was added to thereaction solution. After 1 h, distillation under reduced pressure wascarried out to evaporate THF. Water (100 mmol) was added thereto, andthe resulting solid was filtered. Thus filtered solid was washed with100 ml of water and ethyl acetate/hexane (1:2) solution, and dried togive 3.4 g of the crude product (Purity: 95.9%). This crude product wasrecrystallized from ethyl acetate/hexane/methylene chloride (1:4:1)solution containing 1% methanol to give 2.743 g of carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (CBI) in the purity of99%.

Examples 1 to 6 Preparation of Melt-Extruded Solid Dispersions

Solid dispersions having the compositions of Tables 2 to 7 were preparedfrom a mixture of CBI, a water-soluble polymer and a plasticizer byusing a twin screw having an 18 mm diameter. The mixtures wereintroduced into an extruder wherein four distinguished heating blocks(Zone 1-Zone 4) were connected in series, and the solid dispersionsobtained by melt-mixing and extruding were pulverized by a pulverizer togive the solid dispersions of Examples 1 to 6 as a powder. The detailedpreparation condition is shown in Table 1. Polyvinylpyrrolidone PVP K30was used as the water-soluble polymer. A photograph was taken of the CBIobtained in Preparation 1 (left) and the CBI-containing solid dispersionobtained in Example 1 (right) by Scanning Electron Microscopy as shownin FIG. 1. As can be seen from FIG. 1, in the solid dispersion CBI isuniformly dispersed in the polymer matrix mainly in the form ofamorphous microstructure.

TABLE 1 Parameter Result Extruder Leistritz 18-mm Screw Speed 250 rpmDie Single Bore, Round, 3.0 mm diameter Zone 4 Temperature 75° C. Zone 3Temperature 110° C. Zone 2 Temperature 140° C. Zone 1 Temperature 150°C. Feed Speed of Powder 1.0 kg/hr Feeder Screw 20 mm single flight screwPulverizer Fitzmill L1A Pulverizing Rate 9,000 rpm Standard Sieve 20

TABLE 2 Ingredient Final Composition Ratio (wt %) CBI 15%Polyvinylpyrrolidone 85%

TABLE 3 Ingredient Final Composition Ratio (wt %) CBI 30%Polyvinylpyrrolidone 70%

TABLE 4 Ingredient Final Composition Ratio (wt %) CBI 30%Polyvinylpyrrolidone 69% TPGS 1%

TABLE 5 Ingredient Final Composition Ratio (wt %) CBI 30%Polyvinylpyrrolidone 69% Polyethylene glycol 400  1%

TABLE 6 Ingredient Final Composition Ratio (wt %) CBI 15% Hypromelloseacetate succinate 84% Polyethylene glycol 400  1%

TABLE 7 Ingredient Final Composition Ratio (wt %) CBI 50% Hypromelloseacetate succinate 40% TPGS 10%

Comparative Example 1 Preparation of Melt-Extruded Solid Dispersion

The melt-extruded solid dispersion of Comparative Example 1 was preparedaccording to the same procedure as Example 1 except that thetemperatures of heating blocks were set up as follows. Impurities weremeasured by using the high-performance liquid chromatography for thesolid dispersions of Example 1 and Comparative Example 1. The columnused in the present experiment was a 150 cm×4.6 mm, 3.5 μm C18 column,the flow rate was 1.0 mL/min, the column temperature was 30° C., and thedetection was performed at 260 nm. The mobile phase was applied for 30min under the following gradient condition with acetonitrile and 0.1%aqueous trifluoroacetic acid solution.

TABLE 8 0.1% Aqueous trifluoroacetic Time (Min) Acetonitrile acidsolution  0 Min 45 55 12 Min 45 55 20 Min 80 20 22 Min 45 55 30 Min 4555

As a result, in the case of the solid dispersion of Comparative Example1 which was obtained by warming and melting in Zone 1 whose initialtemperature was the melting point of CBI, decomposition products weregenerated during the procedure and impurities corresponding to theRelative Retention Times (RRTs) of 0.87 and 1.32, the total amountthereof being 6.5%, were detected. However, the total impurity of only0.6% was detected in the solid dispersion of the present invention. Fromthis result, it was confirmed that the preparation method of the presentinvention is a safe method wherein the active ingredient is hardlydecomposed.

TABLE 9 Comparative Example - Heating Block Condition 1 Zone 1 165 Zone2 155 Zone 3 140 Zone 4 90 CBI Content (%) 93.5% Total Impurity (%) 6.5%

Example 7 Preparation of the Solid Dispersion-Containing Tablet

The solid dispersion thus prepared may be formulated into a tablet forthe purpose of easy administration. The tablet was prepared by addingthe pharmaceutically acceptable disintegrating agent, diluent andlubricant as excipients needed for the preparation of a tablet.Specifically, the solid dispersion obtained in Example 2, croscarmellosesodium as a disintegrating agent, magnesium stearate as a lubricant andmicrocrystalline cellulose as a diluent were used. The tablet wasprepared by using SiO₂ for the purpose of increasing fluidity, and theamounts of ingredients are shown in the following Table 10.

TABLE 10 Unit Weight Ratio Ingredient (mg) (%) Function CBI solid 16.76.7 Main ingredient dispersion of Solid dispersion (CBI 30%, Example 2water-soluble polymer 70%) Microcrystalline 217.1 86.8 Diluent Cellulose(Avicel PH102) Croscarmellose 12.5 5 Disintegrating Agent Sodium(Ac-Di-Sol) Magnesium Stearate 1.25 0.5 Lubricant SiO₂ 2.5 1 FluidizerTotal Amount 250 100

Experiment 1 Identification of Solubility of the Active Ingredient CBI

Under several solvent conditions—i.e., distilled water, methanol,ethanol, acetone and diethyl ether—the solubility of CBI was measured.Specifically, about 5 to 40 mg of CBI was introduced into a 1.5 mLmicrotube, and 1 mL of the test solvent was added thereto. The mixturewas slowly stirred in a rotary stirrer for 24 h under the condition ofroom temperature until solvent equilibrium was reached. After stirring,the suspended solution was filtered through a 0.45 micrometer membranefilter. The supernatant was collected and diluted by two-fold with thesame amount of diluent for analysis. The CBI concentration was analyzedby using high-performance liquid chromatography. The column used in thepresent experiment was a 150 cm×4.6 mm, 5 μm C18 column, and the mobilephase was a mixture of 35% acetonitrile, 20% methanol and 45% distilledwater by volume. The flow rate was 1.0 mL/min, and the detection wasperformed at 255 nm. The results are shown in Table 11 wherein thevalues are represented as an average of three repeats ±standarddeviation.

TABLE 11 Solvent Solubility (mg/mL) Distilled Water Not detectedMethanol 2.5 Ethanol 1.5 Diethyl Ether 0.7 Acetone 24.8

From the above results, it is confirmed that CBI is an extremelyinsoluble compound that is hardly dissolved in water.

Experiment 2 Thermal Analysis of CBI

Evaluations of melting point and heat-dependent change ofcharacteristics of CBI were performed by DSC (Differential Scanningcalorimetry). The experimental procedure was briefly explained below. 1to 2 mg of CBI weighed accurately and was introduced into a standardaluminum pan. The temperature was raised from 50° C. to 350° C. at theheating rate of 100° C./min. The thermal characteristics were analyzedunder the nitrogen stream of 25 mL/min. The analysis results are shownin Table 12.

TABLE 12 Melting Point (° C.) Starting Heat of Fusion Sample No.Temperature Peak Time ΔH (J/g) First 164.15 167.94 155.692 Second 164.23167.09 129.708 Average 164.19 167.52 142.700

Experiment 3 Dissolution Test of the Solid Dispersion-Containing Tablet

The solid dispersion-containing tablet obtained in Example 7 wassubjected to a dissolution test according to the second method of UnitedStates Pharmacopoeia Dissolution Test (a paddle method) as follows andthe results are shown in FIG. 2.

Dissolution Test

Method: The second method of United States Pharmacopoeia DissolutionTest (a paddle method)

Dissolution media: 1.5% sodium lauryl sulfate (SLS)-containing distilledwater 500 mL

Stirring speed: 50 rpm

Temperature of eluent: 37±0.5° C.

As can be seen from FIG. 2, the tablet prepared from the soliddispersion of the present invention shows a dissolution rate thatsatisfies the criteria of Dissolution Test of Tablet—i.e., 80% or moredissolution for 45 min. From this result, it can be confirmed that thedissolution characteristic of the highly insoluble CBI has been improvedvery effectively.

Experiment 4 Pharmacokinetic Test of the Solid Dispersion for a BeagleDog

Just before the test, three Beagle dogs were weighed respectively. Thesolid dispersion of Example 3 as the test group and CBI powder as thecontrol group each weighed in the amount corresponding to 40 mg/kg, werefilled into a gelatin capsule and then orally administered. Just beforeand at 0.5, 1, 2, 4, 6, 8 and 24 h after administration, the blood wascollected from the popliteal vein. The plasma was separated from theblood sample by centrifugation and stored/kept at −20° C. until analysisthereof. For the analysis, the plasma sample (0.5 ml) was correctlytransferred to a 1.5 ml polypropylene centrifuge tube. This mixture wasvortexed for 30 sec and centrifuged at 400 rpm for 10 min. Theconcentration of CBI in the plasma was analyzed by LC-MS/MS. As themobile phase, a mixed solution of 0.1% formicacid-acetonitrile/deionized water (60/40, v/v), as the flow rate 0.25mL/min, and as the column Xterr®S C18 (3.0×50 mm, 2.5 micrometer,Waters, USA) were used. The peak was detected by MRM (multiple reactionmonitoring) method using triple-quadrupole mass spectrometry. Theionization was analyzed in the positive mode by using electrosprayionization (ESI) wherein the ion spray temperature was set up at 500° C.In the MRM method, the protonated molecular ions of CBI and the internalstandard compound were monitored to have the m/z values of 325.1 and268.0, and the product ions thus produced were monitored to have the m/zvalues of 91.0 and 155.0, respectively. The area under theconcentration-time curve (AUC) of the drug in the plasma was calculatedby the linear trapezoidal method. The results are shown in the followingTable 13 and FIG. 3.

TABLE 13 Blood CBI Concentration (μg/mL) Time (hours) Test Group ControlGroup 0  0.0 ± 0.0 Below the 0.5 0.080 ± 0.06 Sensitivity for 1 0.464 ±0.28 Quantification 2 0.692 ± 0.33 4 0.183 ± 0.10 6 0.065 ± 0.04 8 0.059± 0.05 24 Not Detected AUClast (μg*hr/mL)  1.98 ± 0.96 AUCInf (μg*hr/mL) 2.14 ± 1.04

As can be seen from the above results, the control group to which CBIpowder was administered shows the result of “below the sensitivity forquantification” in all the time zones, which confirms that the drug wasnot orally absorbed at all. On the contrary, the test group to which thesolid dispersion of the present invention was administered shows themaximum blood concentration of 0.531 μg/mL at 1 h after administration,which confirms that the absorption by oral administration andbioavailability of CBI have been conspicuously improved.

1-29. (canceled)
 30. A method for preparing a solid dispersion,comprising: mixing carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester and a water-solublepolymer, and melt-extruding the mixture at a temperature lower than themelting point of carbamic acid3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester.
 31. The method ofclaim 30, wherein the mixture further comprises a plasticizer.
 32. Themethod of claim 31, wherein the mixture is melted when it passes throughfour or more heating blocks, wherein a temperature of the heating blocksis sequentially lowered.
 33. The method of claim 32, wherein the heatingblocks consist of a first, a second, a third, and a fourth heatingblocks, wherein a temperature of the first heating block is controlledto 160 to 145° C., wherein a temperature of the second heating block iscontrolled to 144 to 120° C., wherein a temperature of the third heatingblock is controlled to 119 to 80° C., and wherein a temperature of thefourth heating block is controlled to 79 to 70° C.